Role of GPX4 in ferroptosis and its pharmacological implication

Abstract

Ferroptosis is a non-apoptotic form of cell death characterized by iron-dependent lipid peroxidation and metabolic constraints. Dependence on NADPH/H⁺, polyunsaturated fatty acid metabolism, and the mevalonate and glutaminolysis metabolic pathways have been implicated in this novel form of regulated necrotic cell death. Genetic studies performed in cells and mice established the selenoenzyme glutathione peroxidase (GPX4) as the key regulator of this form of cell death. Besides these genetic models, the identification of a series of small molecule ferroptosis-specific inhibitors and inducers have not only helped in the delineation of the molecular underpinnings of ferroptosis but they might also prove highly beneficial when tipping the balance between cell death inhibition and induction in the context of degenerative diseases and cancer, respectively. In the latter, the recent recognition that a subset of cancer cell lines including certain triple negative breast cancer cells and those of therapy-resistant high-mesenchymal cell state present a high dependence on this lipid make-up offers unprecedented opportunities to eradicate difficult to treat cancers. Due to the rapidly growing interest in this form of cell death, we provide an overview herein what we know about this field today and its future translational impact.

Keywords: Cysteine metabolism; Ferritinophagy; GPX4; Lipid peroxidation; Non-apoptotic cell death; Regulated necrosis.